Dr David M Iser, Department of Gastroenterology, St. Vincent's Hospital, 41 Victoria Parade, Fitzroy, Vic. 3065, Australia. Email: firstname.lastname@example.org
Coinfection with HIV and hepatitis B virus (HBV) has become a significant global health problem. Liver disease is now one of the leading causes of morbidity and mortality in individuals with HIV, particularly those with viral hepatitis. There are a number of agents available with dual activity against HIV and HBV, and effective treatment depends on understanding the potential advantages and pitfalls in using these agents. There are a number of unresolved issues in the management of HIV/HBV coinfection. These include the role of liver biopsy, the significance of normal aminotransferase levels, serum HBV DNA threshold for treatment, treatment end-points, and the treatment of HBV when HIV does not yet require treatment. Treatment of HBV should be considered in individuals with HIV/HBV coinfection with evidence of significant fibrosis (≥F2), or with elevated serum HBV DNA levels (>2000 IU/mL). Sustained suppression of serum HBV DNA to below the level of detection by the most sensitive available assay should be the goal of therapy, and, at present, treatment of HBV in HIV/HBV coinfection is lifelong. If antiretroviral therapy is required, then two agents with anti-HBV activity should be incorporated into the regimen. If antiretroviral therapy is not required, then the options are pegylated interferon, adefovir or the early introduction of antiretroviral therapy. Close monitoring is necessary to detect treatment failure or hepatic flares, such as immune reconstitution disease. Further studies of newer anti-HBV agents in individuals HIV/HBV coinfection may advance treatment of this important condition.
HIV and hepatitis B virus (HBV) commonly occur together due to shared modes of transmission. HIV/HBV coinfection has become a significant health problem as liver disease has emerged as one of the most important causes of morbidity and mortality among HIV-positive individuals, particularly those coinfected with viral hepatitis.1 There has been a considerable body of evidence published in the area of HIV/HBV coinfection in recent years,2–8 and a number of treatment guidelines have been published by key opinion leaders.9–15 This reflects increased awareness of both the importance of treating HBV to reduce HBV-related morbidity and mortality, and the potential deficiencies in treatment strategies. This review will outline important issues in the current treatment of HIV/HBV coinfection, as well as highlight areas of difficulty and controversy.
Rationale for treatment of HBV in individuals with HIV
Untreated HIV/HBV coinfection is characterized by higher HBV viral loads than HBV monoinfection,16 less frequent seroconversion from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb) positivity,17 and less frequent clearance of acute hepatitis B.14 Although “flares” of aminotransferase (AT) levels are relatively common, AT levels were found to be lower in coinfected individuals in the era before 1996, when highly active antiretroviral therapy (HAART) was introduced.18 Necroinflammatory activity on liver biopsies is less in coinfected individuals, and yet progression of fibrosis is more rapid and development of cirrhosis more common.19 One cross-sectional study showed milder hepatic inflammatory activity but a higher proportion of individuals with advanced fibrosis among those with HIV/HBV coinfection, compared to HBV monoinfection. This indicates possible discordance between the inflammatory process in coinfection and resulting liver injury.19 However, large, well-designed prospective studies are required to confirm these findings.
Patients can experience immune reconstitution flares when commencing antiretroviral therapy (ART).20 These issues highlight the need for effective therapy. There are now a number of agents available with dual activity against HIV and HBV, and effective treatment depends on understanding this.
When and whom to treat
Despite numerous reviews and guidelines for treatment of HBV in HIV coinfected individuals, there are still unresolved issues. These include:
• The role of liver biopsy
• The significance of normal AT levels
• Serum HBV DNA threshold for treatment
• Treatment end-points
• Treatment of HBV when HIV does not yet require treatment.
A lack of prospective data means that many decisions are empiric. A recent survey of clinical practice highlighted some major points of divergence.11
Liver biopsy, histological findings and accelerated fibrosis
Liver biopsy remains the gold standard to assess the degree of hepatic fibrosis. Alternatives include algorithms based on a range of biochemical and hematological indices such as FibroTest, and non-invasive measures of elastic stiffness, such as FibroScan; neither have been studied in HBV or HIV/HBV coinfection.21
Liver biopsy is recommended prior to commencement of HBV therapy, and is a requirement for subsidized treatment in some countries.3,5,12,13 If patients are commencing antiretroviral therapy (ART), liver biopsy may offer useful information about the degree of fibrosis at baseline.4,6,11 The detection of advanced fibrosis allows the institution of intensive hepatocellular carcinoma (HCC) screening, and screening for esophageal varices. It also identifies patients at risk of decompensation with immune reconstitution flares when ART is commenced. Unexpectedly advanced fibrosis and alternative diagnoses are also occasionally made by liver biopsy although this probably occurs in less than 15% of biopsies.22 In many countries, especially developing countries where the burden of disease is greatest, the cost and practicalities involved in performing liver biopsy are prohibitive, and decisions regarding ART need to made without histological information.2
The significance of elevated serum alanine aminotransferase (ALT) levels in the setting of HIV/HBV coinfection is complex. A number of studies in HBeAg-positive monoinfection have shown greater therapeutic responses to either interferons or nucleoside analogs in the setting of elevated ALT levels.23,24 However, significant fibrosis can occur in the absence of high AT levels. In the REVEAL-HBV cohort, 94% of 3653 HBsAg-positive Taiwanese participants followed for a median of 11 years had normal baseline ALT levels.25 Despite normal ALT levels, a high risk of HCC and cirrhosis was observed among those with serum HBV DNA levels of 2000 IU/mL or more (104 copies/mL, where 1 IU ∼5 copies), highlighting HBV viral load as being a critical determinant of disease progression.25 The observation that lower ALT levels are found in HIV/HBV coinfection compared to HBV monoinfection may reflect impaired HBV-specific immunity.19 Furthermore, traditional “normal” ranges for ALT may not be appropriate for Asian people with lower body fat levels. In addition, hepatic necroinflammatory activity is lower in coinfected individuals and this is consistent with observations that ALT levels are lower in coinfected individuals. Finally, ALT levels are dynamic and variations over time can reflect a number of potential causes, such as immune reconstitution flares, drug-induced liver injury or superinfection with hepatitis C or D.2
In summary, few guidelines and reviews warn of the potential for significant hepatic fibrosis despite apparently normal ALT levels in HIV/HBV coinfected persons.4,15 Normal ALT levels should be viewed with particular caution in the presence of high HBV DNA levels. Liver biopsy is therefore still recommended, regardless of ALT level, and particularly before a decision is made to defer or commence treatment of HBV and/or HIV.
In HBV monoinfection, there is strong evidence that the incidence of cirrhosis is related to the level of viremia. The REVEAL-HBV study group demonstrated that individuals with HBV DNA of 200 000 IU/mL were 10 times more likely to develop cirrhosis than those with undetectable HBV DNA at baseline, over a mean follow up of 11 years.26 In the same study, individuals with HBV DNA above 2000 IU/mL had 2.5 times increased risk of cirrhosis. Whether this is relevant in HIV/HBV coinfection, where HBV viral loads are frequently higher, is unclear.
Previous guidelines for the treatment of HIV/HBV coinfection recommend the use of thresholds that are used for HBV monoinfection:5,12,27
• HBeAg-positive disease: HBV DNA of more than 20 000 IU/mL (105 copies/mL)
• HBeAg negative disease: HBV DNA more than 2000 IU/mL
• Underlying cirrhosis: HBV DNA more than 200 IU/mL.
However, because coinfected individuals are at greater risk of liver disease, we recommend a threshold for treatment of 2000 IU/mL for all non-cirrhotic individuals and 200 IU/mL in the presence of cirrhosis.14 Monitoring of HBV DNA should ideally take place every 3 or 6 months for treated and untreated individuals, respectively.28
Goals of therapy
In HBV monoinfection, the primary goal of therapy is to prevent long-term complications of cirrhosis and HCC by sustained suppression of viral replication to the lowest possible level (undetectable HBV DNA by sensitive polymerase chain reaction assay).29 In HBeAg-positive chronic hepatitis B (CHB), a possible end-point is seroconversion from HBeAg positivity to HBeAb positivity if this is combined with undetectable HBV DNA. In HBeAg-negative CHB, treatment is usually lifelong, and aimed at sustained viral suppression.
In HIV/HBV coinfection, the aim should also be sustained HBV suppression with undetectable HBV DNA by the most sensitive available assay. The strategy used depends upon the need for ART, as based primarily on CD4 criteria, where ART is recommended for individuals with a CD4 count of less than 350 cells/μL9 If ART is required, then agents with HBV activity are incorporated into the ART regimen, and effectively combination HIV/HBV therapy is used. If ART is not required, then the strategy is to use agents with exclusive HBV and no HIV activity so that HIV resistance is not induced. As in HBV monoinfection, the long-term goal is to prevent cirrhosis and HCC.7,12,27 However, an additional aim is to minimize ART-associated hepatotoxicity. The ultimate serological end-point of HBsAg seroconversion is rarely achieved in HIV/HBV coinfection but may occasionally allow consideration to withdraw HBV treatment.11 Discontinuation of HBV therapy 6 months after HBeAg seroconversion may be an option. However, there is no evidence to support the durability of seroconversion in a coinfection setting, and this strategy cannot be currently recommended. The traditional biochemical end-point of ALT suppression to normal levels has been used in the past as a surrogate end-point in therapeutic trials. However, this is unlikely to be a sufficient indicator of virological control in coinfection, and in most circumstances treatment of HBV with HIV/HBV coinfection should be lifelong.5,12
Agents approved against HBV
There are currently eight agents approved for use against HBV (Table 1).
Table 1. Anti-hepatitis B virus (HBV) and HIV activity of currently available drugs
Interferon and pegylated interferon (PEG-IFN) have not been found to cause HIV resistance mutations, but typically decrease serum HIV RNA levels by ∼1 log10 viral copies/mL.
Interferons: standard interferon (1992) and pegylated interferon (2005)
Standard interferons (IFN) have only been studied in small open-label studies, which found poor response rates in HIV/HBV coinfection, probably due to immune deficiency.30,31 Pegylated (PEG)-IFN has not been studied in HIV/HBV coinfection apart from one study which examined the combination of PEG-IFN and tenofovir.32 However, PEG-IFN is superior to standard IFN in HBV monoinfection and weekly administration is better tolerated than thrice weekly standard IFN.33 The efficacy of PEG monotherapy in coinfection in the era of HAART with preserved CD4 counts is not known. PEG-IFN is safe and effective in HIV/HCV coinfection, and can be used in patients with high CD4 counts where ART is not recommended.34
Despite PEG-IFN having a modest anti-HIV effect, there is no known or theoretical risk of developing drug-resistant HIV.35 Therefore, 48 weeks of either 180 μg PEG-IFN-α-2a or 100 μg PEG-IFN-α-2b once a week injection, as used in HBV monoinfection, may be used. The HBeAg seroconversion and viral suppression rate is likely to be lower than the 24–32% seen in monoinfection.33,36 However, the finite duration of treatment and the lack of potential for drug resistance make PEG-IFN an attractive option.
Pegylated-IFN can lead to significant lymphopenia, and therefore a decrease in CD4-positive T cells, as well as thrombocytopenia. It is therefore unlikely to be well tolerated in patients with low CD4 counts.
In the APRICOT study, which compared standard IFN and PEG-IFN in HIV/HCV coinfection, the incidence of hepatic decompensation among patients with cirrhosis was 10.4% (14/134).37 There were six deaths due to hepatic decompensation, all in patients with Child–Pugh scores of 6 or more.37 PEG-IFN should therefore be used with caution in patients with cirrhosis, and is contraindicated in those with decompensated liver disease.
Lamivudine is an L-nucleoside analog like emtricitabine and telbivudine, and therefore shares cross-resistance with these drugs. Lamivudine is the most extensively studied agent against HBV (at 100 mg/day), and also has good anti-HIV activity (at 300 mg/day). It is well tolerated, with few adverse effects and is highly efficacious against HBV.38 However, the barrier to resistance is low so that the rate of drug resistance is as high as 20% per year in HBV monoinfection.39 Resistance rates of 50% after 2 years and 90% after 4 years have been reported in coinfected patients.40
Lamivudine has been widely used against HIV, and ART-experienced individuals are likely to have had prolonged previous lamivudine exposure with a concomitant high probability of HBV drug resistance.41 Lamivudine promotes the selection of isolates with mutations in the HBV polymerase at a number of sites in the YMDD motif, such as rtM204V/I, which can predispose to cross-resistance to other L-nucleosides (emtricitabine, telbivudine and clevudine).42 Furthermore, common lamivudine-resistant mutations, rtL180M and rtM204V, are two of the three mutations required for entecavir resistance, while another mutation, rtA181T/VA, confers cross-resistance to adefovir.10 A triple polymerase mutant (rtL173V, rtL180M, rtM204V), which behaves as a HBV-vaccine escape mutant in vitro, has been reported in up to 17% of people with HIV/HBV coinfection treated with long-term lamivudine.40 In conclusion, monotherapy with lamivudine should be avoided, and this agent should always be used in conjunction with tenofovir as part of ART for coinfected individuals.
Adefovir dipivoxil is a nucleotide analog delivered as a phosphorylated pro-drug. Adefovir demonstrates anti-HIV activity at 120 mg, but at this dose unacceptable rates of nephrotoxicity occurred.43 A reduced dose of 10 mg/day is now therefore used in patients with lamivudine-resistant HBV.44 Adefovir shows efficacy against both wild-type and lamivudine-resistant HBV.45 It is useful in the treatment of HBV in coinfected patients whose HIV is suppressed on ART or in patients who do not require ART. While no HIV mutations have been found when adefovir is used as monotherapy in the setting of uncontrolled HIV replication, concern about potential HIV mutations persist when this agent is used without ART.46
There are also concerns about the potency of adefovir, because a proportion of patients will experience minimal HBV suppression over 48 weeks; this may increase the risk of developing adefovir as well as lamivudine resistance.47 HBV resistance to adefovir occurs less frequently than lamivudine resistance. However, mutations at rtN236T and rtA181V, which confer resistance, have been described at rates of up to 29% after almost 5 years.48 These mutations are partially cross-resistant to tenofovir, and the rt181V is partially cross-resistant to lamivudine.10 The rate of resistance is markedly reduced when adefovir is added to lamivudine rather than used as sequential monotherapy in lamivudine-resistant HBV.49
Entecavir is a guanosine analog which is highly active against HBV at a dose of 0.5 mg/day. A randomized control trial in HBeAg-positive nucleoside analog-naive HBV monoinfected patients showed more frequent histological improvement (72% vs 62%, P = 0.009), ALT normalization (68% vs 60%, P = 0.02), undetectable HBV DNA (67% vs 36%, P < 0.001), but no difference in HBeAg seroconversion when compared to lamivudine over 48 weeks.50 In a similar trial in HBeAg-negative patients, entecavir was also superior to lamivudine.51
No genotypic resistance was reported in these original trials. However, a small proportion of patients (22/673, 3%) did experience virological rebound, and genotypic resistance has since been described.52 A number of entecavir-related mutations have been reported, but drug resistance appears to depend on the presence of at least three: rtL180M and rtM204V and either rt184G/S, rtS202I or rtM250V. The first two mutations are recognizable as conferring lamivudine resistance, while changes at position 184 also occur in patients on lamivudine.53 As a result, entecavir resistance is more common in lamivudine-experienced patients, and a higher dose of 1 mg is recommended in this context.
Entecavir was originally heralded as potent anti-HBV therapy with no anti-HIV effect in vitro, and therefore was said to pose no risk of developing HIV mutations.54 Unfortunately, clinical use of entecavir has been associated with a 1 log reduction of HIV viral load in some patients.55 Use of entecavir in the absence of ART in HIV/HBV coinfection has also been associated with the appearance of a mutation in HIV polymerase (M184V) which confers resistance to lamivudine and emtricitabine. This mutation corresponds with the HBV polymerase mutation of rtM204V also conferring lamivudine resistance. Further experiments have shown that entecavir is a potent, partial inhibitor of HIV, and that the M184V mutation confers resistance to entecavir.55 For this reason, entecavir should not be used as monotherapy for HBV in a coinfection setting. Rather, it should be reserved for HBV-infected patients whose HIV is well controlled on ART.
Agents approved against HIV that have anti-HBV activity
Emtricitabine (FTC) is a cytosine analog which is phosphorylated intracellularly to emtricitabine 5′-triphosphate. It is similar structurally to lamivudine and therefore its resistance profile and efficacy against HIV and HBV are similar.56,57 Emtricitabine and lamivudine should be considered interchangeable, and emtricitabine offers no advantage in the setting of lamivudine resistance.
Tenofovir disoproxil fumarate is an adenosine nucleotide analog like adefovir, but with good efficacy and safety profile in the treatment of HIV. Subgroup analyses of large trials have demonstrated an anti-HBV effect in both treatment-naive and lamivudine-resistant HBV.58 It has recently been reported that tenofovir results in more potent viral suppression than adefovir (91% vs 56% with undetectable HBV DNA, P < 0.001) among HBeAg-negative HBV monoinfected patients treated for 48 weeks.59
Retrospective analyses comparing tenofovir and adefovir in coinfected patients, and one small prospective randomized study have observed a greater decline in HBV DNA using tenofovir than adefovir.60 The dual antiviral activities of tenofovir, favorable side-effect profile, and high genetic barrier to resistance have made it an attractive option for treating both viruses in HIV/HBV coinfection. However, long-term prospective data in this setting are lacking. Co-formulations of tenofovir and emtricitabine (Truvada) are now often used as first-line therapy for HIV; this allows for the use of effective combination HBV therapy in the setting of coinfection.
A novel HBV polymerase mutation (rtA194T) has been reported in patients with HIV/HBV coinfection taking tenofovir for longer than 12 months.61 When present in combination with lamivudine-resistant mutations, rtL180M and rtM204V, this mutation conferred reduced susceptibility in vitro, but has not yet been associated with clinical or virological treatment failure. The incidence of this mutation has not yet been determined prospectively. Tenofovir has been associated with hypophosphatemia and renal impairment. Therefore, renal function and serum phosphate levels should be monitored every 3 months.62
Pegylated-IFN plus lamivudine has been studied in HBV monoinfection and confers no advantage over PEG-IFN monotherapy.36,63 However, significantly less lamivudine-resistance was observed in the combination arm compared to lamivudine monotherapy; 4% versus 27% (P < 0.001) in HBeAg-positive patients,36 and 1% versus 18% (P < 0.001) in HBeAg-negative patients.63 The role of combination interferons and nucleos(t)ide analogs in coinfection is not known and cannot be currently recommended.
With nucleos(t)ide analogs, there is consistent evidence that combination therapy can result in the prevention of drug resistance. Combination therapy with adefovir and lamivudine resulted in less virological breakthrough and fewer YMDD mutations (2% vs 20%) than lamivudine monotherapy over 52 weeks in a prospective randomized study of 115 treatment-naive patients with CHB.64 Furthermore, in patients with lamivudine resistance, the addition of adefovir to lamivudine in 145 consecutively treated patients (73% with cirrhosis) was associated with rates of de novo rtA181T of only 1%, 2%, 4% and 4%, at 1, 2, 3 and 4 years, respectively.49 Much higher rates of adefovir resistance have been reported in patients with lamivudine-resistant HBV treated with adefovir monotherapy, up to 22% at 2 years.10,65,66
In HIV/HBV coinfection, one study compared initial combination therapy with tenofovir and lamivudine (n = 25) with sequential monotherapy of lamivudine and tenofovir (n = 50).67 There was no significant difference in HBeAg loss or viral suppression (<2000 IU/mL) between the two groups. The partially retrospective study design and the fact that patients in the sequential monotherapy arm had been on lamivudine for a median of almost 4 years as part of ART, means that comparison of “baseline” data may not be valid. This period of immune restoration also meant that patients in the sequential monotherapy arm had significantly higher CD4 counts than patients in the combination therapy arm. In light of these data, it is recommended that combination HBV therapy, preferably with tenofovir and either lamivudine or emtricitabine should be used in the context of HIV/HBV coinfection whenever possible.
Telbivudine (Food and Drug Administration approved 2006)
Telbivudine (L-deoxythymidine, LdT) is a L-nucleoside thymidine analog which is currently available in the USA, Europe and parts of Asia. Telbivudine produces a more profound reduction in HBV DNA than lamivudine (6.01 log10 IU/mL vs 4.57 log10 IU/mL, P < 0.05) and undetectable HBV DNA at a higher rate (61% vs 32%, P < 0.05) after 52 weeks of therapy in monoinfected individuals. Unfortunately, telbivudine and lamivudine share cross-resistance, so that combination therapy with lamivudine and telbivudine was actually less effective than telbivudine monotherapy.68 With in vitro studies, telbivudine had no effect on HIV replication, but clinical experience is lacking. A high rate of resistance is likely to limit its clinical utility, and telbivudine cannot therefore be recommended for treatment of HBV in coinfection at this stage.
Treatment of HBV where HIV treatment not yet required
The most difficult situation for the treatment of HBV in the setting of HIV coinfection is where HBV requires treatment but HIV does not yet meet treatment criteria. The decision to treat should be made guided by the algorithm in Figure 1. In general, HBeAg-positive patients should be considered for treatment with PEG-IFN. Adefovir is another alternative, although it has limited potency in some patients, and there is a theoretical risk of HIV mutations, as described earlier. An alternative is to consider the early introduction of ART with anti-HBV activity, especially when CD4 counts are between 350–500 cells/μL10,69 Entecavir should not be used to treat HBV in individuals with HIV/HBV coinfection unless HIV is well controlled on ART, as outlined earlier.
Treatment of HBV and HIV
When a patient meets the criteria for introduction of ART according to current guidelines for HIV monoinfection,70 the situation is simplest when patients are naive to therapy for both viruses. Two agents against HBV should be included.7,69,70 The most commonly chosen option is tenofovir in combination with either emtricitabine or lamivudine. Tenofovir and emtricitabine are co-formulated as Truvada and with efavirenz as Atripla. If tenofovir cannot be tolerated, then other options would include either adefovir or entecavir in combination with either emtricitabine or lamivudine. If emtricitabine/lamivudine cannot be tolerated, then tenofovir in combination with entecavir is another option.
If lamivudine-resistant HBV is present, lamivudine should be continued for lamivudine-resistant HIV which has reduced viral fitness in vitro and slower progression in vivo. Tenofovir is active against lamivudine-resistant HBV, but long-term experience with adefovir suggests that lamivudine/emtricitabine should be continued to reduce the risk of tenofovir resistance.49,71 Entecavir is another option, but less preferred because lamivudine resistance predisposes to entecavir resistance, as discussed earlier (Fig. 2).10,53
Monitoring of treatment response and for drug resistance
Monitoring of clinical progress, ALT levels, and virological suppression via HBV DNA levels, is generally performed every 3 months. The presence of detectable HBV DNA after 24 weeks of therapy may be an important indicator of treatment failure, and add-on therapy should be considered at this stage.10 Patients should be educated to present at any time they develop symptoms of hepatic flares, such as dark urine, jaundice, profound malaise or upper abdominal pain. Patients with cirrhosis should also be educated about signs of hepatic decompensation such as jaundice, bleeding, ascites or early encephalopathy, for example, as indicated by disturbance of the sleep–wake cycle.
Individuals with HBV and HIV are at higher risk of developing HCC than HBV monoinfected patients.72,73 To detect early (treatable) HCC, screening with 6–12 monthly liver ultrasound and serum α-fetoprotein (AFP) measurement is frequently offered, although a review of available trials led the authors to conclude that there was insufficient evidence to support or refute the benefit of HCC screening.74 Problematic issues are that only two-thirds of tumors produce AFP,75 and the effect of lead-time bias is difficult to eliminate from trial data when attempting to estimate any survival benefit of HCC screening. Nevertheless, some patients with HCC may be cured with hepatic resection or liver transplantation,76 and it is for this reason that screening is still usually practised.11
Screening for esophageal varices by gastroscopy is also recommended in patients with cirrhosis, although whether variceal band ligation or beta-blockers are better as primary prophylaxis is debated.77 Referral to a liver transplant or gastroenterology unit is recommended for the management of patients with decompensated cirrhosis.
All individuals with HIV should be screened for HBV coinfection before commencing ART. Effective treatment of HBV in HIV coinfection is largely based upon extrapolation of data from HBV monoinfection, and observation in small studies of coinfected patients. PEG-IFN should be considered in HBeAg-positive patients not yet requiring ART. Nucleos(t)ide analog monotherapy should be avoided due to the possibility of developing either or both HBV or HIV drug resistance. For patients who require ART, combination therapy using agents with dual HIV and HBV activity is recommended aiming for long-term viral suppression. Where possible, liver biopsy should be considered before starting therapy and monitoring should include quantitative HBV DNA testing by the most sensitive available assay every 3 months. Studies of recent additions to the HBV therapeutic armamentarium in HIV/HBV coinfection may improve the long-term management of this condition.
David Iser receives funding from the National Health and Medical Research Council (NHMRC) and has received grants from Altana Pharma, Wyeth Australia, Astra-Zeneca and Roche Pharmaceuticals. Joseph Sasadeusz has received grants and honoraria from and sits on the advisory boards of Roche Pharmaceuticals, Gilead Sciences, Merck Pharmaceuticals, Novartis and Bristol Myers Squibb.